Freeze-drying, also known as lyophilization, is a process for drying high-quality products such as, for example, pharmaceuticals, biological materials such as proteins, enzymes, microorganisms, and in general any thermo- and/or hydrolysis-sensitive materials. Freeze-drying provides for drying of the target product via sublimation of ice crystals into water vapor, i.e., via the direct transition of at least a portion of the water content of the product from the solid phase into the gas phase.
Freeze-drying processes in the pharmaceutical area may be employed, for example, for the drying of drugs, drug formulations, Active Pharmaceutical Ingredients (“APIs”), hormones, peptide-based hormones, carbohydrates, monoclonal antibodies, blood plasma products or derivatives thereof, immunological compositions including vaccines, therapeutics, other injectables, and in general substances which otherwise would not be stable over a desired time span. In order for a freeze-dried product to be stored and shipped, the water (or other solvent) has to be removed prior to sealing the product in vials or containers for preserving sterility and/or containment. In the case of pharmaceutical and biological products, the lyophilized product may be re-constituted later by dissolving the product in a suitable reconstituting medium (e.g., pharmaceutical grade diluent) prior to administration, e.g., injection.
A freeze-dryer is generally understood as a process device employed in a process line for the production of freeze-dried particles such as granules or pellets with sizes ranging typically ranging from several micrometers to several millimeters. Freeze-drying may be performed under arbitrary pressure conditions, e.g., atmospheric pressure conditions, but may efficiently (in terms of drying time scales) be performed under vacuum conditions (i.e., defined low-pressure conditions).
Drying the particles as bulkware may generally provide for a higher drying efficiency than drying the particles after filling into vials or containers. Various approaches for (bulk) freeze-dryer designs comprise employing a rotary drum for receiving the particles. The effective product surface may be increased by the rotating drum which may lead, in turn, to an accelerated mass and heat transfer as compared to drying the particles in vials or as bulkware dried in stationary trays. Generally, bulk drum-based drying can lead to homogeneous drying conditions for the entire batch.
DE 196 54 134 C2 describes a device for freeze-drying products in a rotatable drum. The drum is filled with the bulk product and is slowly rotated in order to achieve a steady heat transfer between product and inner wall of the drum. The inner wall of the drum can be heated by a heating means provided in the annular space between the drum and a chamber housing the drum. Cooling can be achieved by a cryogenic medium inserted into the annular space. The vapor released by sublimation from the product is drawn off the drum. In this approach a vacuum is provided inside the drum, which leads to a complex mechanical configuration wherein, for example, a vacuum pump has to be connected in a vacuum-tight manner (vacuum-sealed) to the interior of the rotating drum. Further, any equipment (or supply lines thereto) related to cooling, heating, sensing of process conditions, cleaning, and sterilization has to be adapted to preserve the vacuum-tight property of the rotary drum.
For efficient freeze-drying under vacuum conditions, sublimation of vapor from the particles may include maximizing effective product surface area by rotation of a drum and be further promoted by providing, for example, optimized process conditions for the particles. For example, a heating mechanism may be provided in the chamber and/or drum to keep the temperature near an optimum value during freeze-drying.
One of the problems that can occur during efficiently driven freeze-drying processes is that the escaping vapor when drawn out of the drum/process chamber can attain detrimentally high velocities. In fact, the flow of escaping sublimation vapor may cause “choked flow conditions” (also sometimes referred to as “choke flow conditions”), wherein the velocity of the escaping vapor approaches a physically determined fixed maximum value, i.e., becomes choked, as it leaves the drum. However, in many instances the interaction between the vapor flow and the particles in the drum gets stronger as the particles become smaller. As a consequence, for pellets or granules in the sub-millimeter size range the interaction becomes powerful enough that the escaping vapor at or near choked flow conditions can sweep an undesirably large fraction of the product out of the drum. Besides negatively affecting production efficiency in terms of lost product, problems associated with bulk dryness may occur such as insufficiently dried particles carried out of the drum subsequently mixed during discharging with the sufficiently dried particles. Problems with cleaning and/or sterilization can also occur.
Some of these problems can be ameliorated by decreasing the velocity (or mass) of the vapor flow, and thereby the momentum which is transferred to particles crossing the flow inside the rotating drum. However, such approaches generally come at the cost of substantially decreasing drying efficiency in terms of drying times. For example, measures such as adapting the vacuum conditions to reduce the escape velocities of the vapor, controlling a lower temperature within the process volume, and/or reducing the effective product surface by slowing down the rotation of the drum, all tend to lengthen the time required to obtain the desired level of product dryness.